Endogenous opioid system contributions to anti-depressant action

内源性阿片系统对抗抑郁作用的贡献

基本信息

批准号：
9520638
负责人：
Rene Hen
金额：
$ 21.5万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-12 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9520638
关键词：
Acute Affect Agonist Analgesics Anatomy Antidepressive Agents Behavioral Binding Biological Assay Brain region Chronic Complex Corpus striatum structure Data Development Dorsal Enkephalin Receptors Enkephalins Fluoxetine Gene Expression Genes Genetic study Hippocampus (Brain)Injections Knockout Mice Ligands Mediating Mental Depression Mental disorders Molecular Mus Neprilysin Opiate Addiction Opioid Opioid Receptor Patients Peptides Pharmacology Positioning Attribute Resistance Selective Serotonin Reuptake Inhibitor Site Sodium Chloride Specificity Swimming System Testing Treatment outcome Up-Regulation antidepressant effect behavioral response delta opioid receptor dentate gyrus depressive symptoms endogenous opioids experimental study feeding ineffective therapies inhibitor/antagonist mu opioid receptors novel novel strategies proenkephalin receptor response tianeptine

项目摘要

Current treatments for depression have limitations that significantly impact treatment outcomes. One is that a large percentage (~40%) of patients are resistant to any current treatment. Evidence now indicates that the endogenous opioid system may represent a previously under-appreciated system that can yield novel anti-depressant treatments. We will extend recent preliminary data to test this possibility directly. We will first test the hypothesis that deletion of proenkephalin-derived peptides alters the behavioral and molecular responses to chronic fluoxetine. We have recently demonstrated that the known antidepressant tianeptine is an agonist of the mu opioid receptor (MOR). We and others have also found that expression of the proenkephalin (Penk) gene, which encodes a precursor to an endogenous MOR ligand, is dramatically up regulated in the dentate gyrus following chronic treatment with several SSRIs. These findings suggest that Penk peptides may be central components in the molecular response to anti-depressant treatment. We will test this possibility by determining whether chronic behavioral anti-depressant activities of fluoxetine are altered or abolished in Penk KO mice. We will further determine the extent to which previously-determined gene expression changes in response to chronic fluoxetine are altered in Penk KO mice and thus begin to position Penk up-regulation in this molecular cascade. Our second aim will test the hypothesis that pharmacologic up-regulation of enkephalin peptides in specific brain regions is sufficient to promote behavioral responses to SSRIs. Systemic injection of enkephalinase inhibitors can produce anti-depressive and analgesic actions resulting from enkephalin peptide up-regulation, though the cellular sites of activity have remained undefined. Our preliminary experiments indicate that RB-101 rapidly increases analgesic activity following icv injection. We will extend these studies to examine acute anti-depressant effects of RB-101 injection directly into several brain regions in both WT and Penk deficient mice. This pharmacologic approach will thus mimic one specific molecular response to chronic SSRI treatment and thus begin to determine whether increased Penk alone is sufficient to mediate anti-depressant responses as well as identify the specific brain regions that can mediate such effects. Finally, we will identify the opioid receptor specificity of increased enkephalin action. Enkephalin can bind the delta opioid receptor (DOR) as well as MOR and these opioid system components are co- expressed in the hippocampus, a major locus implicated in anti-depressant action. We will compare anti- depressive actions of RB-101 in MOR, DOR and MOR/DOR KO mice following injection into multiple brain regions to determine whether responses are altered in the absence of either or both receptors. These studies will thus identify the receptor(s) mediating enkephalin activities and begin to develop a more detailed understanding of the circuitry underlying opioid system activity in anti-depressive action.

目前抑郁症的治疗方法存在局限性，会严重影响治疗结果。一很大一部分（~40%）患者对目前的任何治疗都有抵抗力。现在的证据表明内源性阿片类药物系统可能代表了一个以前被低估的系统，它可以产生新的抗抑郁治疗。我们将扩展最近的初步数据来直接测试这种可能性。我们将首先测试以下假设：删除脑啡肽原衍生肽会改变行为以及对慢性氟西汀的分子反应。我们最近证明了已知的抗抑郁药噻奈普汀是一种 mu 阿片受体 (MOR) 激动剂。我们和其他人还发现编码内源性 MOR 配体前体的脑啡肽原 (Penk) 基因的表达是在长期使用几种 SSRIs 治疗后，齿状回的表达显着上调。这些研究结果表明 Penk 肽可能是抗抑郁药物分子反应的核心成分治疗。我们将通过确定慢性行为抗抑郁活动是否有效来测试这种可能性 Penk KO 小鼠中氟西汀的含量发生改变或消除。我们将进一步确定在多大程度上 Penk KO 中先前确定的响应慢性氟西汀的基因表达变化发生改变小鼠，从而开始在该分子级联中定位 Penk 上调。我们的第二个目标将检验以下假设：脑啡肽的药理学上调特定的大脑区域足以促进对 SSRI 的行为反应。全身注射脑啡肽酶抑制剂可以产生由脑啡肽产生的抗抑郁和镇痛作用上调，但细胞活性位点仍未确定。我们的初步实验表明 RB-101 在 ICV 注射后迅速增加镇痛活性。我们将扩展这些研究检查直接注射 RB-101 到几个大脑区域的急性抗抑郁作用 WT 和 Penk 缺陷小鼠。因此，这种药理学方法将模仿一种特定的分子长期 SSRI 治疗的反应，从而开始确定单独增加 Penk 是否足以介导抗抑郁反应，并确定可以介导此类作用的特定大脑区域。最后，我们将确定增加脑啡肽作用的阿片受体特异性。脑啡肽可以结合 δ 阿片受体 (DOR) 以及 MOR，这些阿片系统成分共同作用在海马体中表达，海马体是与抗抑郁作用有关的主要部位。我们将比较反 RB-101 对 MOR、DOR 和 MOR/DOR KO 小鼠注射多只后的抑郁作用大脑区域以确定在缺少其中一个或两个受体的情况下反应是否会改变。这些因此，研究将确定介导脑啡肽活性的受体，并开始开发更详细的了解阿片类药物系统抗抑郁作用的潜在电路。